The present invention relates to new naphthyl- and anilide-substituted sulphonamides, processes for their preparation and their use as antiviral agents, in particular against cytomealoviruses.
xcex1,xcex2-Naphthyl-linked phenylsulphonamides are mainly disclosed in phototechnical publications [cf. for this purpose JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, U.S. Pat. No. 3,925,347, U.S. Pat. No. 4,035,401, U.S. Pat. No. 3,622,603, U.S. Pat. No. 3,482,971, EP-284 130].
WO 90/09 787 discloses sulphonamides as radio- or chemosensitizing agents and their use in the treatment of tumours.
The compound N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]phenyl]-acetamide is additionally known (J. Inst. Chem. (India) (1976), 4S. Pt 6, 280-5).
The present invention relates to new naphthyl- and anilide-substituted sulphonamides of the general formula (I) 
in which
R1 and R2 are identical or different and represent hydrogen, formyl, phenyl or benzyl optionally substituted by one to three halogen atoms, or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, where alkyl or acyl can optionally be substituted by one to three substituents selected from halogen and hydroxyl,
A, D, E and G are identical or different and represent hydrogen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
R3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which optionally carries an amino group which can optionally be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, halogen, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or
R3 represents radicals of the formula 
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group having up to 6 carbon atoms,
Q represents alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl, or
represents radicals of the formula 
xe2x80x83in which
a denotes the number 1 or 2,
R5 denotes hydrogen,
R6 denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or denotes straight-chain or branched alkyl having up to 8 carbon atoms,
where the alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula xe2x80x94NR9R10 or R11xe2x80x94OCxe2x80x94,
xe2x80x83in which
R9 and R10 independently of one another denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,
and
R11 denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group xe2x80x94NR9R10,
or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which, for its part, is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group xe2x80x94NR9R10,
xe2x80x83in which
R9 and R10 have the meaning indicated above,
or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding xe2x80x94NH functions are optionally substituted by alkyl having up to 6 carbon atoms or protected by an amino protective group,
R7 and R8 are identical or different and denote hydrogen or an amino protective group,
R4 represents hydrogen or a radical of the formula 
xe2x80x83in which
R5xe2x80x2, R6xe2x80x2, R7xe2x80x2 and R8xe2x80x2 have the meaning of R6, R7 and R8 indicated above and are identical to or different from this,
X has the meaning of R4 indicated above and can be identical to or different from this meaning,
and their stereoisomers, stereoisomeric mixtures and salts,
with the exception of N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]phenyl]acetamide.
In a preferred embodiment, the invention relates to sulphonamides of the above general formula (I), in which
R1 and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms
A, D, E and G are identical or different and represent hydrogen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
R3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms. which optionally carries an amino group which can be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, halogen, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or
R3 represents radicals of the formula 
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group having up to 6 carbon atoms,
Q represents alkyl having up to 6 carbon atoms, which is optionally substituted by carboxyl, or represents radicals of the formula 
xe2x80x83in which
a denotes the number 1 or 2,
R5 denotes hydrogen,
R6 denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or denotes straight-chain or branched alkyl having up to 8 carbon atoms,
where the alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a croup of the formula xe2x80x94NR9R10 or R11xe2x80x94OCxe2x80x94,
xe2x80x83in which
R9 and R10 independently of one another denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,
and
R11 denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group xe2x80x94NR9R10,
or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms which, for its part, is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group xe2x80x94NR9R10,
xe2x80x83in which
R1 and R10 having the meaning indicated above,
or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding xe2x80x94NH functions are optionally substituted by alkyl having up to 6 carbon atoms or protected by an amino protective group,
R7 and R8 are identical or different and denote hydrogen or an amino protective group,
R4 represents hydrogen or a radical of the formula 
xe2x80x83in which
R5xe2x80x2, R6xe2x80x2, R7xe2x80x2 and R8xe2x80x2 have the meaning of R5, R6, R7 and R8 indicated above and are identical to or different from these, and
X represents hydrogen,
and their stereoisomers, stereoisomeric mixtures and salts,
with the exception of N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]-phenyl]acetamide.
Further preferred compounds are sulphonamides of the above general formula (I), in which
R3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, in which the alkyl carries an amino group which can be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is identically or differently substituted one to 3 times by hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl which. for its part, can be identically or differently substituted up to 2 times by nitro, halogen or hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or
R3 represents radicals of the formula 
xe2x80x83in which L and Q are as defined above, and X preferably represents hydrogen.
Further preferred compounds of the invention are sulphonamides of the above general formula (I), in which
R1 and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms,
A, D, E and G are identical or different and represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, hydroxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
R3 represents straight-chain or branched alkenyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 7 carbon atoms, which optionally carries an amino group which can be substituted by alkyl having up to 3 carbon atoms, tert-butyloxycarbonyl or benzyloxycarbonyl, or the alkyl is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, azido, nitro, trifluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine, chlorine or hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 3 carbon atoms, or
R3 represents radicals of the formula 
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms,
Q represents alkyl having up to 4 carbon atoms, which is optionally substituted by carboxyl, or represents radicals of the formula 
xe2x80x83in which
a denotes the number 1 or 2,
R5 denotes hydrogen,
R6 denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or denotes straight-chain or branched alkyl having up to 6 carbon 10 atoms.
where the alkyl can optionally be substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H2Nxe2x80x94COxe2x80x94,
or the alkyl is substituted by cyclohexyl, naphthyl or phenyl which, for its part, can be substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms,
or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding xe2x80x94NH functions are optionally substituted by alkyl having up to 4 carbon atoms or protected by tert-butyloxycarbonyl or benzyloxycarbonyl,
R7 and R8 are identical or different and denote hydrogen, tert-butyloxycarbonyl or benzyloxycarbonyl,
R4 represents hydrogen or a radical of the formula 
xe2x80x83in which
R5xe2x80x2, R6xe2x80x2, R7xe2x80x2 and R8xe2x80x2 have the meaning of R5, R6, R7 and R8 indicated above and are identical to or different from this, and
X preferably represents hydrogen,
and their stereoisomers, stereoisomeric mixtures and salts
with the exception of N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]phenyl]acetamide.
Further preferred compounds of the invention are sulphonamides of the above general formula (I), in which
R3 represents straight-chain or branched alkenyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 7 carbon atoms, in which the alkyl carries an amino group which can be substituted by alkyl having up to 3 carbon atoms, tert-butyloxycarbonyl or benzyloxycarbonyl, or the alkyl is identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, azido, nitro, trifluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine. chlorine or hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 3 carbon atoms, or
R3 represents radicals of the formula 
xe2x80x83and in which L and Q are as defined above
X preferably represents hydrogen,
Further preferred compounds of the invention are sulphonamides of the above general formula (I), in which
R1 and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
A, D, E and G are identical or different and represent hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl or methoxy,
R3 represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 carbon atoms, which optionally carries an amino group which can be substituted by tert-butyloxycarbonyl or benzyloxycarbonyl, or which is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, nitro, azido, trifluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine, chlorine, hydroxyl, methyl, ethyl, methoxy or ethoxy, or
R3 represents radicals of the formula 
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms,
Q represents alkyl having up to 3 carbon atoms, which is optionally substituted by carboxyl, or represents a radical of the formula 
xe2x80x83in which
R5 denotes hydrogen,
R6 denotes cyclopentyl, cyclohexyl or hydrogen, or denotes straight-chain or branched alkyl having up to 4 carbon atoms,
where the alkyl can optionally be substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H2Nxe2x80x94COxe2x80x94,
or the alkyl is substituted by cyclohexyl, naphthyl or phenyl which, for its part, can be substituted by fluorine. chlorine or alkoxy having up to 4 carbon atoms,
or the alkyl is substituted by indolyl, imidazolyl, triazolyl, pyridyl or pyrazolyl, where the corresponding xe2x80x94NH functions are optionally substituted by methyl or protected by benzyloxymethylene or tert-butyloxycarbonyl (BOC),
R7 and R8 are identical or different and denote hydrogen or tert-butyloxycarbonyl,
R4 represents hydrogen or a radical of the formula 
xe2x80x83in which
R5xe2x80x2, R6xe2x80x2, R7xe2x80x2 and R8xe2x80x2 have the meaning of R5, R6, R7 and R8 indicated above and are identical to or different from these, and
X preferably represents hydrogen,
and their stereoisomers, stereoisomeric mixtures and salts,
with the exception of N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]phenyl]acetamide.
Further preferred compounds of the invention are sulphonamides of the above general formula (I), in which
R3 represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 carbon atoms, in which the alkyl carries an amino group which can be substituted by tert-butyloxycarbonyl or benzyloxycarbonyl, or the alkyl is identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, nitro, azido, trifluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine, chlorine, hydroxyl. methyl, ethyl, methoxy or ethoxy, or
R3 represents radicals of the formula 
xe2x80x83in which L or Q are as defined above, and
X preferably represents hydrogen,
and their stereoisomers, stereoisomeric mixtures and salts.
Further particularly preferred compounds of the invention are sulphonamides of the above general formula (I), in which
R1 and R2 represent straight-chain or branched alkyl having up to 4 carbon atoms,
A, D, E and G represent hydrogen,
R3 represents straight-chain or branched alkyl having up to 5 carbon atoms, which is substituted by hydroxyl, or
R3 represents a radical of the formula
xe2x80x94Lxe2x80x94Oxe2x80x94COxe2x80x94Q
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms,
Q represents a radical of the formula 
xe2x80x83in which
R5 and R6 denote hydrogen, and
R7and R8 denote hydrogen, and
R4 represents hydrogen, and
X preferably represents hydrogen,
and their stereoisomers, stereoisomeric mixtures and salts.
Very particularly preferred compounds of the invention are sulphonamides which are selected from the group of the following compounds: 
The invention furthermore relates to a process for the preparation of compounds of the above general formula (I), which is characterized in that
[A] compounds of the general formula (I) 
xe2x80x83in which
A, D, E, G, R1 and R2 have the meaning indicated above,
are first converted by catalytic hydrogenation on palladium/C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (III) 
xe2x80x83in which
A, D, E, G, R1 and R2 have the meaning indicated above,
and these are finally reacted with compounds of the general formula (IV)
xe2x80x83Txe2x80x94COxe2x80x94R3xe2x80x83xe2x80x83(IV)
xe2x80x83in which
R3 has the meaning indicated above
and
T represents hydroxyl or halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base and/or of an auxiliary,
or
[B] compounds of the general formula (V) 
xe2x80x83in which
E, G, R3 and R4 have the meaning indicated above,
are first converted as described under [A] by hydrogenation on Pd/C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (VI) 
xe2x80x83in which
E, G, R3 and R4 have the meaning indicated above,
and these are finally reacted with compounds of the general formula (VII) 
xe2x80x83in which
A, D, R1 and R2 have the meaning indicated above
and
V represents halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base and/or of an auxiliary,
or
[C] if R3 and/or R3xe2x80x2 represent a radical of the formula xe2x80x94Lxe2x80x94Oxe2x80x94COxe2x80x94Q, compounds of the general formula (Ia) 
xe2x80x83in which
R1, R2, R4, A, D, E, G and L have the meaning indicated above,
are reacted with amino acid residues of the general formula (III)
.HOxe2x80x94COxe2x80x94Qxe2x80x2xe2x80x83xe2x80x83(VIII)
xe2x80x83in which
Qxe2x80x2 has the meaning of Q indicated above, where one of the terminal radicals on the nitrogen, mentioned there, represents one of the abovementioned protective groups, preferably tert-butyloxycarbonyl,
if appropriate with activation of the carboxylic acid according to customary methods, in inert solvents and in the presence of a base and of an auxiliary,
and finally the protective group is removed according to the methods customary in peptide chemistry,
and in the case in which X, R4xe2x89xa0H is reacted with 2 or more equivalents of the compounds of the general formula (VIII),
if appropriate the stereoisomers are separated according to methods known per se and if appropriate the free bases are converted into the salts or the salts are converted into the free bases.
The invention furthermore relates to sulphonamides of the above general formula (I) for the prophylaxis or treatment of diseases.
The invention furthermore relates to the use of sulphonamides of the above general formula (I) for the production of medicaments, in particular medicaments for the control of viral disorders and preferably medicaments for the control of cytomegalovirus.
The invention finally relates to medicaments comprising sulphonamides of the above general formula (I).
The substances according to the invention can also be present as salts. In the context of the invention physiologically acceptable salts are preferred.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, dior triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
By the term xe2x80x9calkanediyl groupxe2x80x9d, hydrocarbon groups are indicated here which are linked to further radicals in two positions. Preferably, these linkage sites are located on different carbon atoms.
Examples of alkanediyl groups are: xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94 etc.
Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry.
These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3 ,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1,1-dimethylethoxy-carbonyl, adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl; 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitroberizyl or 4-nitrophenyl.
The compounds of the general formula (I) according to the invention can occur in different stereochemical forms, which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
With respect to the amino acid residue, the compounds of the general formula (I) according to the invention can be present either in the D or L form, and the R or S configuration. The invention includes the optical antipodes as well as the isomer mixtures or racemates.
In the context of the invention, the compounds of the general formula (I) according to the invention can be bonded to the naphthyl structure in the xcex1- or xcex2-position in relation to the xe2x80x94SO2xe2x80x94NX-group and the NHxe2x80x94COxe2x80x94R3 group can be linked to the phenyl ring in the o-, m- or p-position. 
Preferably, the xe2x80x94SO2xe2x80x94NX group is bonded to the naphthyl structure in the in xcex1- or xcex2-position and the xe2x80x94NR4xe2x80x94COxe2x80x94R3 group is bonded to the phenyl radical in the m- or p-position.
Particularly preferably, the xe2x80x94SO2xe2x80x94NX group is bonded to the naphthyl structure in the xcex1-position and the xe2x80x94NR4xe2x80x94COxe2x80x94R3 group is linked to the phenyl radical in he p-position.
Particularly preferred compounds are shown in Table A:
The particularly preferred compounds shown in Table A can be present in the form of the free base, as pharmaceutically acceptable salts, in particular hydrochlorides, or optionally as zwitterions.
The compounds of the general formula (I) according to the invention can be prepared by a process in which
[A] compounds of the general formula (II) 
xe2x80x83in which
A, D, E, G, R1 and R2 have the meaning indicated above,
are first converted by catalytic hydrogenation on palladium/C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (III) 
xe2x80x83in which
A, D, E, G, R1 and R2 have the meaning indicated above,
and these are finally reacted with compounds of the general formula (IV)
Txe2x80x94COxe2x80x94R3xe2x80x83xe2x80x83(IV)
xe2x80x83in which
R3 has the meaning indicated above
and
T represents hydroxyl or halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base and/or of an auxiliary,
or
[B] compounds of the general formula (V) 
xe2x80x83in which
E, G, R3 and R4 have the meaning indicated above,
are first converted as described under [A] by hydrogenation on Pd/C or by reduction with SnCl2 in inert solvents into the compounds of the general formula (VI) 
xe2x80x83in which
E, G, R3 and R4 have the meaning indicated above,
and these are finally reacted with compounds of the general formula (VII) 
xe2x80x83in which
A, D, R1 and R2 have the meaning indicated above
and
V represents halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base and/or of an auxiliary,
or
[C] if R3 and/or R3 represent a radical of the formula xe2x80x94Lxe2x80x94Oxe2x80x94COxe2x80x94Q, compounds of the general formula (Ia) 
xe2x80x83in which
R1, R2, R4, A, D, E, G and L have the meaning indicated above,
are reacted with amino acid residues of the general formula (VIII)
xe2x80x83HOxe2x80x94COxe2x80x94Qxe2x80x2xe2x80x83xe2x80x83(VIII)
xe2x80x83in which
Qxe2x80x2 has the meaning of Q indicated above, where one of the terminal radicals on the nitrogen, mentioned there, represents one of the abovementioned protective groups, preferably tert-butyloxycarbonyl,
if appropriate with activation of the carboxylic acid according to customary methods, in inert solvents and in the presence of a base and of an auxiliary,
and finally the protective group is removed according to the methods customary in peptide chemistry,
and in the case in which X, R4xe2x89xa0H is reacted with 2 or more equivalents of the compounds of the general formula (VIII),
The process according to the invention can be illustrated by way of example by the following reaction schemes: 
Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, e.g. diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydro furan, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, pyridine and dioxane are particularly preferred.
Suitable bases are organic amines, in particular trialkyl(C1-C6)amines such as, for example, triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Pyridine, triethylamine and N-methylmorpholine are preferred.
In general, the bases are employed in an amount from 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case relative to I mol of the compounds of the general formulae (III) and (IV).
Suitable auxiliaries are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonic anhydride or isobutyl chloroformate or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphora-midate or methanesulphonyl chloride, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.
The reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). In general, they are carried out at normal pressure.
The reactions are carried out in a temperature range from 0xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 30xc2x0 C. and at normal pressure.
In general, the reductions can be carried out by means of hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenohydrocarbons, or their mixtures, using catalysts such as Raney nickel, palladium, palladium on animal charcoal or platinum, or using hydrides such as SnCl2, or boranes in inert solvents, if appropriate in the presence of a catalyst. Palladium on animal charcoal or SnCl2 is preferred.
The reaction can be carried out at normal, elevated or at reduced pressure (e.g. 0.5 to 5 bar). In general, it is carried out at normal pressure.
In general, the reductions are carried out in a temperature range from 0xc2x0 C. to +60xc2x0 C., preferably at +10xc2x0 C. to +40xc2x0 C.
Suitable solvents for the acylation are customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and pyridine are preferred.
The acylation is carried out in the abovementioned solvents at temperatures from 0xc2x0 C. to +150xc2x0 C., preferably at room temperature to +100xc2x0 C. and at normal pressure.
Suitable solvents for process [C] are customary organic solvents which do not change under the reaction conditions. These preferably include organic solvents such as alcohols, e.g. methanol, ethanol or n-propanol, ethers, for example, diethyl ether, glycol mono- or -dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenohydrocarbons such as methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane, dimethylformamide and n-propanol are particularly preferred.
Auxiliaries employed for the respective peptide couplings are preferably condensing agents, which can also be bases, in particular if the carboxyl group is present activated as an anhydride. Preferably, the customary condensing agents are employed here such as carbodiimides, e.g. N,Nxe2x80x2-diethyl-, Nxe2x80x2-dipropyl-, N,Nxe2x80x2-diisopropyl-, N,Nxe2x80x2-dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate, or 1-hydroxybenzotriazole and as bases, alkali metal carbonates, e.g. sodium or potassium carbonate, or sodium or potassium hydrogencarbonate, or organic bases such as trialkylamines, e.g. triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine. Dicyclohexyl-carbodiimide, N-methylmorpholine and 1-hydroxybenzotriazole are particularly preferred.
The amino protective group is removed in a manner known per se under acidic or basic conditions, or reductively by catalytic hydrogenation, for example using Pd/C in organic solvents such as ethers, e.g. tetrahydrofuran or dioxane, or alcohols, e.g. methanol, ethanol or isopropanol.
The amino protective groups can also be removed by customary methods using acids, such as, for example, hydrochloric acid or trifluoroacetic acid.
In general, the reactions are carried out in a temperature range from xe2x88x9220xc2x0 C. to +80xc2x0 C., preferably from 0xc2x0 C. to +60xc2x0 C.
In general, the reaction is carried out at normal pressure. However, it is also possible to work at reduced pressure or at elevated pressure (e.g. from 0.5 to 5 bar).
The compounds of the general formula (VIII) are known.
The compounds of the general formula (Ia) are new and can be prepared as shown above under processes [A] and [B].
The compounds of the general formulae (II). (III), (IV), (V), (VI) and (VII) are known per se or can be prepared by methods known from the literature.
The present invention additionally includes the use of N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]amino]phenyl]acetamide as an antiviral agent, in particular against cytomegaloviruses.
The compounds of the general formulae (I) and (Ia) according to the invention exhibit an unforeseeable surprising spectrum of action. They exhibit an antiviral action against representatives of the herpesviridae group, particularly against human cytomegalovirus (HCMV). They are thus suitable for the treatment and prophylaxis of disorders which are caused by herpes viruses, in particular disorders which are caused by human cytomegalovirus (HCMV).
The anti-HCMV action was determined in a screening test system in 96-well microtitre plates with the aid of human embryonic lung fibroblast (HELF) cell cultures. The effect of the substances on the spread of the cytopathogenic effect was determined in comparison with the reference substance ganciclovir (Cymevene(copyright) sodium), a clinically approved anti-HCMV chemotherapeutic.
The substances dissolved (50 mM) in DMSO (dimethyl sulphoxide) are investigated on microtitre plates (96-well) in duplicate determinations (4 substances/plate). Toxic and cytostatic substance effects are additionally detected at the same time. After the appropriate substance dilutions (1:2) on the microtitre plate, a suspension of 50-100 HCMV-infected HELF cells and 30xc3x97105 non-infected HELF cells in Eagle""s MEM with 10% foetal calf serum is added to each well, and the plates are incubated at 37xc2x0 C. in a CO2 incubator for several days. After this time, the cell lawn in the sub-stance-free virus controls, starting from 50-100 infectious centres, is completely destroyed by the cytopathogenic effect of the HCMV (100% CPE). After staining with Neutral Red and fixing with formalin/methanol, the plates are assessed with the aid of a projection microscope (plaque-viewer). The results are summarized for some compounds in the following table:
It has now been found that the compounds according to the invention inhibit the replication of the HCMV in HELF cells in concentrations which are in some cases 10- to 50-fold lower than Cymeven(copyright) sodium and have a selectivity index which is several times higher.
The compounds according to the invention are thus valuable active substances for the treatment and prophylaxis of disorders which are caused by human cytomegalovirus.
Examples of indication areas which may be mentioned are:
1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who suffer from HCMV pneumonitis or encephalitis and also from gastrointestinal and systemic HCMV infections, often with life-threatening consequences.
3) Treatment and prophylaxis of HCMV infections in new-born children and infants.
4) Treatment of an acute HCMV infection in pregnant women.
Animals
5 week-old male mice, NOD/LtSz-Prkdc(scid)/J strain, were obtained from a commercial breeder (The Jackson Lab., Bar Harbor). The animals were kept in isolators under sterile conditions (including litter and feed).
Virus/infection
Murine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB/c) and purified by means of fractional centrifugation. The titre was investigated with the aid of a plaque assay for primary embryonic mouse fibroblasts. The mice were infected with a dose of 5xc3x97105 pfu in a total volume of 0.2 ml intraperitoneally. This dose leads to death in 100% of the infected animals after about 11 days.
Treatment/assessment
24 hours after infection, the mice were treated orally with substance twice daily (morning and evening) over a period of 8 days. The dose was 25 mg/kg of body mass, the administration volume 10 ml/kg of body mass. The substances were formulated in the form of a 0.5% strength Tylose suspension. 16 hours after the last substance administration, the animals were painlessly killed and the salivary gland, liver and kidney were removed.
Genomic DNA was purified from 25 mg of the tissue by means of phenol/chloroform extraction. The DNA was quantified photometrically and with the aid of the formula
OD260xc3x9750=mg/ml.
The purity of the DNA was checked by means of the quotient OD260/OD280 and the DNA was then adjusted to pH=8.0 using tris-EDTA.
The MCMV-DNA was quantified by means of DNA dot blot hybridization. The probe used was a digoxygenin-labelled (Boehringer-Mannheim, also the buffers mentioned, if not described otherwise) 1.2 kb fragment from the MCMV region, Smith, HindIII J. The signals were detected by means of chemoluminescence. For this purpose, the membrane was washed for 3 minutes in 1xc3x97digoxygenin-wash buffer 1. Following this, the filters were incubated at room temperature for 30 minutes in 1xc3x97digoxygenin blocking solution with shaking. The filters were then incubated with the anti-DIG alkaline phosphatase conjugate solution (1:20000 in 1xc3x97digoxygenin blocking solution) for 30 minutes in 20 ml/100 cm2 membrane. 2 washing steps with 1xc3x97digoxygenin-wash buffer lasting 15 minutes each then took place. A 5 minute equilibration of the filters in 1xc3x97digoxygenin detection buffer and detection by means of 1 ml/100 cm2 membrane surface area of 1:100 diluted CDP star solution followed. After streaking out the CDP star solution and incubation for 5 minutes in a dark box, chemoluminescence was detected or assessment was carried out by means of X-ray film (Kodak) or Lumilmager (Boehringer Mannheim).
All results were confirmed statistically (variance analysis by means of statistics StatSoft Inc.).
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this case, the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifying agents and/or dispersing agents, it being possible, for example, if water is used as a diluent, optionally to use organic solvents as auxiliary solvents.
Administration is carried out in a customary manner, preferably orally, parenterally or topically, in particular perlingually, intravenously or intravitreally, if appropriate as a depot in an implant.
In the case of parenteral administration, solutions of the active compounds using suitable liquid carrier materials can be employed.
In general it has proved advantageous in the case of intravenous administration to administer amounts from approximately 0.001 to 10 mg/kg, preferably approximately 0.01 to 5 mg/kg, of body weight to achieve effective results, and in the case of oral administration the dose is approximately 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, mainly depending on the body weight or on the type of administration route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual administrations over the course of the day.
If appropriate, it may be useful to combine the compounds according to the invention with other active substances.
Eluent Mixtures: